| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073071 |
| E.1.2 | Term | Hepatocellular carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041823 |
| E.1.2 | Term | Squamous cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To characterize the safety and tolerability and to identify the recommended Phase 2 dose (RP2D) of ALKS 4230 administered subcutaneously (SC) as lead-in monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors (Phase 1)
- To characterize the safety profile of SC ALKS 4230 at the RP2D in combination with pembrolizumab in subjects with advanced solid tumors (Phase 2)
- To estimate the clinical activity of combination treatment with ALKS 4230 and pembrolizumab in terms of objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1 separately for non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), squamous tumor agnostic, hepatocellular carcinoma (HCC), and small-cell lung cancer (SCLC) (Phase 2) |
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| E.2.2 | Secondary objectives of the trial |
- To describe dose-limiting toxicity (DLT) for SC ALKS 4230 lead-in monotherapy (Phase 1)
- To characterize the pharmacokinetics (PK), clinical pharmacodynamics (PD), and immunogenicity of SC ALKS 4230 as lead-in monotherapy (Phase 1) and in combination with pembrolizumab (Phase 1 and Phase 2)
- To describe antitumor activity observed with SC ALKS 4230 as lead-in monotherapy and in combination with pembrolizumab (Phase 1)
- To evaluate antitumor efficacy in subjects treated with SC ALKS 4230 in combination with pembrolizumab (Phase 2) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is aged ≥18 years.
2. Subject or the subject’s legal representative provides written informed consent.
3. For Phase 1, Subject must have an advanced solid tumor (including lymphoma) and progressive disease following at least 1 line of therapy.
4. For Phase 2, subject must have one of the following tumor types or specific histology:
• NSCLC cohort: Subjects with Stage IIIB or IV NSCLC who have been treated with checkpoint inhibitors with stable disease or better and followed by progression more than 120 days after initiation of the checkpoint inhibitor therapy.
• SCCHN cohort: Subjects with recurrent or metastatic SCCHN with disease progression on or after chemotherapy and who have not received prior checkpoint inhibitor therapy.
• Squamous tumor agnostic cohort: Subjects with recurrent or metastatic squamous cell carcinoma following chemotherapy and who have not received prior checkpoint inhibitor therapy. Patients with SCCHN should enroll in the SCCHN cohort if they meet those eligibility criteria.
• HCC cohort: Subjects with recurrent or metastatic HCC with disease progression on or after antitumor therapy who have not received prior checkpoint inhibitor therapy.
• SCLC cohort: Subjects with unresectable or metastatic SCLC who have progressed on or after a minimum of 4 cycles of chemotherapy which may have included maintenance checkpoint inhibitor therapy. Subjects who have received prior checkpoint inhibitor therapy and had stable disease or better and who subsequently progressed are eligible provided that the progression was more than 120 days of the initiation of checkpoint inhibitor therapy.
5. Subject must have measurable disease based on RECIST.
6. Subject must have completed the last dose of any broad spectrum antibiotic at least 30 days prior to first dose.
7. Subject has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.
8. Subject has adequate hematologic reserves, measured within 10 days prior to start of study treatment, as evidenced by:
• Absolute neutrophil count of ≥1000/μL without growth factor support in prior month,
• Absolute lymphocyte count of ≥500/μL,
• Platelet count of ≥75,000/μL without platelet transfusion support in prior month, and
• Hemoglobin of ≥9 g/dL (subjects may be transfused to this level if necessary).
9. Subject has adequate hepatic function as evidenced by aspartate transaminase and alanine aminotransferase values ≤3 × the upper limit of normal (ULN) (≤5 × ULN if the liver is known to be involved by metastatic disease) and serum total bilirubin values of ≤1.5 × ULN (≤2 × ULN for subjects with known Gilbert’s syndrome) for the reference laboratory measured within 10 days prior to start of study treatment.
10. Subject has adequate renal function as evidenced by a serum creatinine ≤1.5 × ULN for the reference laboratory or a calculated creatinine clearance of ≥45 mL/min by the Cockroft-Gault equation measured within 10 days prior to start of study treatment.
11. Subject has recovered from the effects of any prior chemotherapy, immunotherapy, other prior systemic anticancer therapy, radiotherapy, or surgery (ie, toxicity no worse than Grade 1 [any grade alopecia and treatment-associated peripheral neuropathy are acceptable]).
12. Subject who has received standard or investigational agents must wait at least 5 half-lives or 4 weeks, whichever is shorter, before enrollment into the study or 4 weeks if the half-life of the investigational agent is not known. Subjects may be enrolled within 3 weeks of previous treatment upon agreement between Medical Monitor and Principal Investigator.
13. Subject who has received wide-field radiotherapy (eg, >30% of marrow-bearing bones) must have completed at least 4 weeks before starting study drug or subject who has received focal radiation must be completed at least 2 weeks before starting study drug.
14. Women of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days of the start of treatment and also on Day 1 before the first dose is administered.
15. Subject meets contraceptive requirements defined in Section 8.4.2. Women of childbearing potential must use at least 1 highly effective form of birth control throughout the study and for 120 days after the last dose of study treatment. All male subjects whose partners are WOCBP must agree to use an acceptable method of contraception for the duration of the study and for at least 120 days after the final dose of study drug unless they are surgically sterile.
16. Subject has international normalized ratio OR prothrombin time ≤1.5× ULN unless the subject is receiving anticoagulant therapy and prothrombin time or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants.
17. Subjects enrolled in the dose expansion part of the study (Phase 2) must agree to provide archival tumor tissue biopsy sample(s) if available. |
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| E.4 | Principal exclusion criteria |
1. Subject is currently pregnant or breastfeeding or is planning to become pregnant during the study period.
2. Subject is employed by Alkermes, Syneos Health, the Investigator, the study center (including permanent or temporary contact workers and designees responsible for the conduct of the study), or other affiliate of this study or is immediate family of an employee of Alkermes, Syneos Health, the Investigator, the study center, or other affiliate. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
3. Subject has an active infection or a fever ≥38.5°C (≥101°F) within 3 days of the first scheduled day of dosing for the monotherapy lead-in or Cycle 1 of Phase 2.
4. Subject has known hypersensitivity (Grade ≥3) to any components of ALKS 4230, to pembrolizumab, or any of its excipients.
5. Subjects with mean QT interval corrected by the Fridericia Correction Formula values of >470 msec (in females) or >450 msec (in males) following a standard 12-lead electrocardiogram (ECG); subjects who are known to have congenital prolonged QT syndromes; or subjects who are on medications known to cause prolonged QT interval on ECG.
6. Subject has developed autoimmune disorders while on prior immunotherapy, including pneumonitis, nephritis, and neuropathy. Subject was discontinued from prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, or CD137) due to a Grade 3 or higher immune-related AE.
Subjects who developed other autoimmune disorders of Grade ≤3 may enroll if the disorder has resolved and the subject is off steroids for 2 weeks. Subjects who experienced autoimmune colitis as a toxicity of prior immunotherapy must undergo or must have been evaluated by colonoscopy to rule out ongoing inflammation.
7. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
8. Subject has active or symptomatic central nervous system metastases unless the metastases have been treated by surgery and/or radiation therapy, the subject has been dose, and the subject is neurologically stable.
9. Subject has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
10. Subject is known to be positive for human immunodeficiency virus and/or history of hepatitis B, or C infections or is known to be positive for hepatitis B antigen (HBsAg)/hepatitis B virus (HBV) DNA or hepatitis C antibody (Hep C Ab) or RNA.
11. Subject requires pharmacologic doses of corticosteroids (greater than 10 mg of prednisone daily, or equivalent); however, replacement doses, topical, ophthalmologic, and inhalational steroids are permitted. Use of glucocorticoids for the purpose of treating immune-mediated AEs is permitted (see Section 9.8) but may result in discontinuation from study based on consultation between the Investigator and the Medical Monitor. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
12. Subject has had a second malignancy within the previous 3 years. This criterion does not apply to subjects with an adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, prostate cancer Gleason score <6 with undetectable prostate-specific antigen over the previous 12 months, breast carcinoma in situ with full surgical resection, or treated medullary or papillary thyroid cancer.
13. Subject has any other concurrent uncontrolled illness, including mental illness or substance abuse, which may interfere with the ability of the subject to cooperate and participate in the study. Other examples of such conditions would include unstable, poorly controlled, or severe hypertension; clinically significant pericardial effusion; New York Heart Association Class III or IV (see Appendix 1: New York Heart Association Heart Disease Classifications) congestive heart failure; known cardiopulmonary disease, defined as unstable angina, myocardial infarction, or cardiovascular accident within 6 months of first dose; chronic obstructive pulmonary disease or diabetes mellitus that has required 2 or more hospitalizations in the last year; severe peripheral vascular disease; or recent serious trauma.
14. Subject has received a live vaccine within 30 days of planned start of study therapy.
15. Subject has active uncontrolled coagulopathy. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- The incidence and severity of treatment-emergent AEs (Phase 1 and Phase 2)
- ORR based on RECIST 1.1 (Phase 2) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Treatment-emergent AEs will be evaluated during every visit at the clinic.
Antitumor activity will be determined by the measurement of extent of
known disease at baseline and approximately every 9 weeks. After Cycle 10, this should be reduced to every 12 weeks. |
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| E.5.2 | Secondary end point(s) |
- The incidence of DLTs from the first dose through the end of the DLT observation period (Phase 1)
- Serum concentrations of ALKS 4230 and descriptive PK parameters using noncompartmental analysis (Phase 1)
- Detection of presence of anti-ALKS 4230 antibodies in serum (Phase 1)
- Numbers of circulating cluster of differentiation (CD)8 T cells, T regulatory cells (Tregs), and natural killer cells in peripheral blood (Phase 1)
- Serum levels of interleukin-6 and other cytokines (Phase 1)
- ORR, Disease Control Rate (DCR), Duration of Response (DOR), Time to Response (TTR),and Progression-free Survival (PFS) per RECIST 1.1 (Phase 1)
- Immune ORR (iORR), immune DCR (iDCR), immune DOR (iDOR), immune TTR (iTTR), and immune PFS (iPFS) per Immune RECIST (iRECIST) (Phase 1)
- DCR, DOR, TTR, and PFS, per RECIST 1.1 (Phase 2)
- iORR, iDCR, iDOR, iTTR, and iPFS, per iRECIST (Phase 2)
- Overall Survival (OS) (Phase 2) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Serum samples for evaluation of ALKS 4230 PK and patient immunogenicity will be obtained from each subject at predetermined time points.
Antitumor activity will be determined by the measurement of extent of
known disease at baseline and approximately every 9 weeks. After Cycle 10, this should be reduced to every 12 weeks. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Korea, Republic of |
| Netherlands |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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